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Hypertrophic scars are fibroproliferative disorders of excessive wound healing due to an imbalance between synthesis and degradation and the mechanism leading to hypertrophic scars formation is poorly understood and currently no successful treatment modality exists. We hypothesize epidermal stem cells (ESCs), which could inhibit epidermal fibrosis, plays a substantial contributory role in the pathogenesis of hypertrophic scars. Accepting the hypothesis to be correct, a therapy that inhibits cell and extracellular matrix proliferation can be used to prevent the hypertrophic scars formation. Current therapies are only partially effective and safe because they couldn't inhibit the cell and extracellular matrix proliferation and eliminate other relative factors of hypertrophic scars formation at all, such as: absence of epidermal-mesenchymal interaction, and at the same time inducing death (apoptosis and necrosis) of other normal cells. A more efficient prevention of hypertrophic scars could be achieved using tissue engineering skin enriched with ESCs and introduced recombinant genes into ESCs which could inhibit hypertrophic scars formation.

The mechanisms of fibroproliferation disease (FPD) of the skin, such as keloids and hypertrophic scars, are still unknown. Since mechanical stress appears to be an important factor for FPD generation, we have studied the intervening factors that connect mechanical stress with keloid and scar formation. Hence, we introduce our "neurogenic inflammation hypothesis" in this paper. Our hypothesis is as follows. Mechanical stress, including skin stretching, stimulates mechanosensitive nociceptors on sensory fibers in the skin. Stimulated fibers release neuropeptides, including SP and CGRP, and these peptides bind to the receptors SP-NK1R and CGRP-CGRP1R on various cells in the skin. Moreover, histamine release is upregulated by mast cells. Consequently, activated endothelial cells and vascular smooth muscle cells induce vasodilation and permeabilization of vessels. Cytokine production, including TGFbeta and NGF, is also stimulated by various cells. The neurogenic inflammation and upregulation of TGFbeta would activate fibroblasts through various signals. Interestingly, overexpressed NGF may induce the hyper-release of neuropeptides from sensory fibers, resulting in the accumulation of neuropeptides even in the absence of mechanical stress, once the malignant cycle has started. Moreover, individual differences in FPD generation may be based on differences in reactivity towards neuropeptides, NGF, and other neurotrophins. Hence, neuropeptide antagonists may be effective against FPD. While further experimental studies and clinical confirmation are needed, our hypothesis may provide new insights into the etiology and pathology of FPD of the skin, such as keloids and hypertrophic scars.

Keloid and hypertrophic scars are a type of scarring pathology which is characterised by excess collagen deposition produced during the wound healing process. The mechanism by which this occurs is not understood and although hypertrophic scars can regress spontaneously, keloids do not, and currently no effective treatment exists. In this paper we hypothesise that nitric oxide, a free radical molecule synthesised by numerous mammalian cells, is involved in the formation of these scars. We suggest that the excess collagen production in keloid lesions can be attributed to higher than normal levels of nitric oxide, as the free radical is a known stimulus for fibroblast collagen synthesis. Furthermore, we propose that the basal epidermis is a source of this additional nitric oxide and we discuss this in relation to known histological characteristics of keloid and hypertrophic lesions., (Copyright 2001 Harcourt Publishers Ltd.)